A direct link between a suspected longevity enzyme and the life-extending effects of a calorie restricted diet has strengthened the case for targeting the enzyme to increase healthy lifespan.

Researchers Blanka Rogina and Stephen Helfand at the University of Connecticut Health Center in Farmington have found that an increase in an enzyme called Sir2 extends lifespan in fruit flies, whereas a decrease in Sir2 blocks the life-extending effects of a calorie restricted diet, suggesting a genetic pathway by which caloric restriction extends lifespan.

The findings could further the development of compounds that mimic the benefits of caloric restriction.

"The documentation of a molecular genetic pathway responsible for effecting calorie-restriction-related lifespan extension will be useful for identifying biochemical mediators and drug interventions that can mimic calorie restriction," write the researchers.

Low-cal trigger

Researchers have long known that caloric restriction—a diet limited in caloric intake but with all essential nutrients—can extend lifespan and delay the onset or reduce the incidence of a variety of age-related diseases.

The exact molecular and cellular pathways through which caloric restriction works, however, have proven unclear. It is generally thought that caloric restriction works by triggering a family of enzymes called sirtuins that protect cells and delay cell death.

This hypothesis is based on studies in yeast and worms that have shown that a sirtuin called Sir2 and its homologues are a key lifespan regulator. But while the Sir2 molecular pathway has been linked to calorie availability in yeast, write Rogina and Helfand, it has not been shown to function in the calorie restriction pathway in multicellular organisms.

"Strong case"

For their study, the researchers created strains of flies that either overexpressed or underexpressed Sir2. They found that in four strains in which Sir2 expression was significantly increased, lifespan was extended by as much as 57%.

Conversely, in two other strains in which Sir2 expression was not elevated or was only marginally elevated, lifespan was not extended. The researchers also showed that lifespan cannot be extended by caloric restriction in flies that lack Sir2, providing evidence for a primary role of Sir2 activity in determining longevity.

"Together, these observations make a strong case that calorie restriction extends lifespan in flies by increasing Sir2 activity," write the researchers.

The research is reported in the Proceedings of the National Academy of Sciences (read abstract).